This project seeks to determine whether polymorphisms in the TP53 and MDM2 genes are responsible for early-onset breast and colon cancer in African Americans. This will be accomplished by cancer exome sequencing of tumors from African Americans and Caucasian Americans with defined combinations of genotypes, and comparing the somatic mutation rates between the groups of patients. We will utilize exome capture and high- throughput paired-end sequencing technologies to identify exonic somatic mutations in 160 tumors representing the four combinations of TP53 Pro/Pro vs Arg/Arg genotypes and MDM2 SNP309 T/T vs G/G genotypes. This will allow correlations to be drawn between the numbers and types of somatic mutations, and race, TP53 genotype, and MDM2 genotype, and it will permit the determination of whether differences in mutation rates between the two races can be attributed to the genetic differences at these two loci. The existence of a cause and effect relationship between genotype and phenotype will be tested by constructing isogenic sets of breast and colon cancer cell lines that represent these four genotype combinations and carefully examining the modified cells for augmented or diminished TP53-dependent cell cycle arrest, apoptosis, or mutation rate. PUBLIC HEALTH RELEVANCE: African Americans are diagnosed with breast and colon cancer at early ages more frequently than are Caucasian Americans, however the reasons are not clear. This work will formally prove whether or not specific DNA sequences, which are more common in African Americans than in Caucasian Americans, can pre- dispose individuals to early onset breast or colon cancer, regardless of their race. If the hypothesis put forth in this proposal is validated, these results will provide the basis for identifying individuals that are at high risk for developing breast or colon cancer, and justify deploying more aggressive screening guidelines for those harboring high-risk DNA sequences.